Quality by Design

One of the challenges for downstream processing is reducing development time and also delivering robust processes and qualitative product. To overcome these challenges Boehringer Ingelheim is using platform technologies and adapting those to each product’s needs. How novel manufacturing technologies fit into the platforms or even create a platform itself are evaluated continuously.

For example, RAPPTor™, a miniaturized and automated platform for screening of resins and conditions, has been implemented to reduce material and labor costs during process development. With RAPPTor, 64 conditions in triplicate, which means a total of 192 experiments, can be screened in three days, the company reported.

Other CMOs also noted the use of new resin technologies. Eden Biodesign has introduced CIM® monolith resin technology (BIA Separations) for both chromatographic separation and HPLC analysis of adenoviral products. According to Roger Lias, Ph.D., president of Eden Biodesign, “the technology has increased both the resolution of separation and the speed of operation.”

At Sandoz, PAT initiatives include online HPLC for immediate intermediate quality control, as well as multivariant data analysis to predict quality-related parameters based on a given set of input parameters, and as a tool to optimize and stabilize the yield of process steps. According to Dr. Nachtmann, “applying such methods in one of our lead products resulted in a productivity increase of approximately 30 percent.”

Adoption of Disposables

Most CMOs manufacture multiple products, so the ability to increase flexibility and reduce the time line is a key competitive advantage. “The use of disposables are of great benefit to a multiproduct facility where we have to deal with tight manufacturing scheduling coupled with rapid operational turnaround between contracts and batches,” Daniel Smith, commercial scientific development manager at Cobra Biomanufacturing, explained.

“Disposables enable a reduction in time taken to clean, prepare, and reclean operational hardware allowing the ensuing reduction in cost to be passed directly on to our customers,” he added. Cobra has developed a new process based on the use of sterile disposable technologies at all stages of manufacturing, including a closed-system tangential flow filtration (TFF) step for buffer exchange and a manifold design for product storage and sampling.

Besides speeding up turnaround time between unit operations, the use of disposables also reduces water for injection (WFI) for cleaning. According to Michiel E. Ultee, Ph.D., vice president of process sciences at Laureate Pharma, “Studies have shown that between 50 to 70 percent of WFI goes toward cleaning operations. WFI has a high energy cost.”

Another key benefit of disposable technology adoption is to increase process safety, a fact confirmed by Rene Brecht, Ph.D., vp of process science and manufacturing at ProBioGen, who added that “the risk of cross-contamination in a multiproduct facility is reduced by use of single-use technologies.”

In addition to full disposable upstream equipment, ProBioGen has implemented membrane chromatography, a set of single-use operations for liquid handling (bags, connectors, tubing, pump systems) and another set of single-use operations for filtration (depth filtration, sterile filtration) for downstream purposes. ProBioGen is also planning to establish single-use TFF technology.

Business Impact

The use of these innovative technologies has increased overall process efficiency, productivity, and process robustness. As disposables become widely used in the industry, many CMOs have commented that disposables enable a reduction in GMP-suite turnaround time due to elimination of cleaning requirements, which allows reduction in cost to be passed directly to their customers. The reduced project time line provides flexibility and agility, and CMOs are able to acquire more projects and provide more services.

“For bioreactors, the initial investment cost with disposable systems is substantially lower compared to conventional bioreactors,” explained Prof. Wagner from Rentschler. “In terms of safety, disposable bioreactors greatly reduce the risk of cross-contamination, which is crucial for special applications like cell therapy with human cells for the treatment of cancer and immune system diseases, and production of recombinant biopharmaceutical proteins and vaccines.”

Similar sentiment was echoed by Philip Ridley-Smith, business development and group marketing manager at Cobra, who said, “the design and building of new facilities will benefit from the use of disposable technologies in order to reduce time and cost and provide greater flexibility to the type and range of products that can be manufactured in a single space.

“As more disposable suppliers enter the market and demand increases there should be a decrease in the cost of goods that will reduce the overall production costs. CMOs, and the industry in general, are seeing an increasing trend for the R&D and production of biosimilar products. With these types of products the pressure to reduce the cost of goods is significant and disposable technologies can provide one of the solutions to producing a competitive biosimilar product,” Ridley-Smith concluded.

“Disposables will play an essential role in small-scale GMP environments and in some multiproduct facilities,” Dr. Vucenovic from Boehringer added. “However, stainless steel bioreactors will remain the preferred option for large-volume products.”

According to Dr. Nachtmann from Sandoz, “disposable systems are clearly advantageous for small-scale low-throughput manufacturing enabling high flexibility with lower investment cost. High-throughput development or high-throughput manufacturing at large scale will keep the focus on automated CIP and SIP systems, which are extremely fast, provide reliable quality, and do not need operator interaction.”

However, Dr. Nachtmann also noted that “the setup of disposable systems not only raises general extractables levels, but also needs an installation qualification for each setup. Certainly, disposables can also be implemented in a conventional facility such as capsule filters and bags for transfer small amounts of product.”

While the adoption of disposables reduces cost, it also has an unintended consequence, which is that it lowers the barrier to entry. “The use of disposables is growing as it reduces GMP-suite turnaround times and can help to reduce the cost of goods for a biopharmaceutical product. This is useful for existing manufacturing organizations and their clients. However, what may be key to the CMO industry is that the growing use of disposables also reduces the barriers to entry into this market,” stated Joanne McCudden, Ph.D., director of marketing and sales at SynCo Bio Partners.

“One key barrier has traditionally been the facility set-up costs,” Dr. McCudden explained. “Being able to use disposables in both upstream and downstream production means that the initial capital costs can be reduced. In a competitive marketplace, this poses both a risk and an opportunity to CMOs—CMOs can expand more easily and with lower capital expenditure. However, medium-sized biotech companies, a key market segment to the majority of CMOs, will be able to set up their own facilities more easily too.”

Convenience is a big factor in using disposables in a multipurpose facility, but disposables require great care as noted by Hiroko Tsukamoto, director of marketing at ASPEX, at division of Asahi Glass. “To discard the disposables after use, they need to be cut up and the expenses increase as a result. Therefore, we evaluate the use of disposables on a case-by-case basis.”

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